PROJECT SUMMARY The purpose of this Phase I STTR project is to develop targeted nanoparticles for the combinatorial delivery of nucleic acids and small molecule drugs as therapeutics. We have previously developed a library of novel aminoglycoside-derived polymer nanoparticles capable of simultaneously delivering nucleic acids and small molecule drugs or imaging agents into mammalian cells. The efficacy of the nanoparticle platform for combinatorial nucleic acid and drug delivery will be demonstrated for the treatment of slow-healing / chronic wounds, which will be employed as a test case for this STTR. Slow healing / chronic wounds, including diabetic wounds, do not heal via normal repair mechanisms and present a great challenge to the medical field. Diabetes affected over 425 million adults worldwide in 2018 and is expected to double in the next 20 years. Chronic wounds occur in 15-25% of all patients with diabetes and pose a high risk of amputation if not properly treated. These wounds are characterized by prolonged inflammation, persistent infection, ECM degradation, increase in proteases, senescent cells, and decrease in angiogenesis and stem cells. Although wound care options including topical dressings and antimicrobials, exist for treatment of chronic wounds, the effectiveness of these treatments is inconsistent. In this STTR project, Synergyan, LLC and Arizona State University (ASU) will screen a novel biocompatible polymer nanoparticle library for the targeted co-delivery of therapeutic plasmid DNA and small- molecule enhancers of transgene expression in dermal cells. Our prior work has shown the effectiveness of these nanoparticles for the combinatorial delivery of plasmid DNA and therapeutic drugs in different cell types. We have also developed small-molecule-polymer conjugates for the targeted delivery of plasmid DNA cargo to specific cell types. In the proposed project, we will develop a nanoparticle library targeting slow healing wounds and evaluate these nanoparticles for the co-delivery of plasmid DNA and small molecule drugs in vitro and in vivo. Wound size, barrier function, tissue biomechanical recovery, inflammation, collagen content, re- epithelialization, granulation, blood glucose and insulin levels, and angiogenesis will be evaluated in the diabetic mouse model. The proposed targeted polymer technology, capable of targeting specific cell types for the site- specific delivery of plasmid DNA cargo and small-molecule enhancers, has high translational potential and can be lead to therapeutic benefit in several diseases.